This invention relates to a method for simultaneously synthesizing a compound and isolating the product in a crystallization procedure, which controls particle size.
U.S. Pat. No. 5,314,506, incorporated herein by reference, provides a method of impinging fluid jet streams in a continuous crystallization process to achieve high intensity micromixing of fluids so as to form a homogeneous composition prior to the start of nucleation. This process permits direct crystallization of the high surface area particles of high purity and stability. Particle size may be controlled by varying the concentration of solutions, temperature and velocity of the solution through the jets. With this method it is possible to prepare compounds of 5 to 1000 microns.
WO 00/44468, incorporated herein by reference, describes an apparatus and process for crystallizing submicron-sized particles with the introduction of a sonication probe with impinging jets.
The use of an impinging jet device optionally with a sonication probe to achieve high intensity mixing coupled with a chemical reaction to provide a new chemical compound of controlled particle size of crystalline materials is novel.
The present invention provides a method for preparation and crystallization of pharmaceutical compounds or their intermediates which directly produces high surface area end product crystals with greatly improved stability and purity and thereby eliminates the need for subsequent high intensity milling to meet bioavailability requirements. By removing the need for milling, the novel jet process avoids associated problems of noise and dusting, cuts yield loss, and saves the time and extra expense incurred during milling. It also removes an extra opportunity for personnel contact with a highly potent pharmaceutical agent, or for adverse effects on labile compounds. The small particle size attained with the jet process is consistent within a single run and is reproducible between runs. Reproducibility is an attribute of this process that is not common to xe2x80x9creverse additionxe2x80x9d methods typically used to produce small crystals.
The pure, high surface area particles that result from the jet process also display superior crystal structure when compared to particles formed via standard slow crystallization plus milling methods using the same quality and kind of feed compound. Improvements in crystal structure result in decreases in decomposition rate and therefore longer shelf life for the crystallized product or a pharmaceutical composition containing the crystallized material.
This invention provides a process for preparation and crystallization of a chemical compound in a continuous process.
More particularly, this invention relates to the use of impinging jets to achieve high intensity micromixing of solvents containing chemical reactants so as to produce a chemical reaction which forms a reaction product under high supersaturation conditions leading to a rapid nucleation in a continuous reaction and crystallization process.
Nucleation and precipitation can be initiated by utilizing the effect of temperature reduction on the solubility of the compound to be crystallized in a particular solvent (thermoregulation), or by taking advantage of the solubility characteristics of the compound in solvent mixtures, or by some combination of the two techniques. Further, the product of the reaction will usually be highly insoluble in the final solvent or combination of solvents.
The novel process of this invention provides for the direct crystallization of high surface area particles of high purity and stability.
This invention provides a process for synthesis and crystallization of a chemical compound comprising contacting one or more jet streams of a solution in a first solvent of a first reactive intermediate and one or more jet streams of a solution in a second solvent of a second reactive intermediate, said jet streams impinging to crate high turbulence at their point of impact under conditions of temperatures and pressure which permit reaction of said first and second reactive intermediates to produce a product; and
selecting said first and second solvents so that said product is of limited solubility in a mixture of said first and second solvents; and
said jet streams impinging to create high turbulence at their point of impact and each jet stream having sufficient linear velocity to achieve high intensity micromixing of said solutions followed by reaction of first and second reactive intermediates, followed by nucleation of said product and production of small crystals of controlled particle size.
In another aspect, this invention also provides a process wherein one of said first or second reactive intermediates is a basic intermediate and the other intermediate is an acidic intermediate.
In another aspect, this invention also provides a process wherein one of said first or second reactive intermediates is a zwitterion and the other intermediate is an acid. This invention further provides a process wherein one of said first or second reactive intermediates is a zwitterion and the other intermediate is a base.
In another aspect, this invention also provides a process wherein one of said first or second reactive intermediates is an organic salt form and the other intermediate is a neutralizing acid compound.
In another aspect, this invention also provides a process wherein one of said first or second reactive intermediates is an organic salt form and the other intermediate is a neutralizing basic compound.
This invention also provides a process, wherein said synthesis results in the forming or breaking of a covalent bond and wherein the product or its corresponding salt form crystallizes.
This invention also provides a process wherein said first solution is a pharmaceutical salt form solution and said second solution is a solution containing either an acid or a base. For example, a solution of Voriconazole camphorsulfonate may be reacted with a solution of sodium acetate to produce Voriconazole free base with controlled particle size. Such a reaction is known as free-basing or conversion to the free base. The process also applies to the conversion to free acids by treating a pharmaceutical salt form with acid to form the free acid. Salt forms include, but are not limited to, those compounds containing anions such as hydrochloride, acetate, besylate, citrate, hydrobromide, D or L lactate, mesylate, succinate, camphorsulfonate, sulfate, D or L tartrate, stearates, tosylates, and cations such as calcium, potassium, sodium and ethylenediamine.
In another aspect, this invention provides a process wherein said chemical compound to be formed is a pharmaceutically acceptable salt form with an ion component selected from the group consisting of: hydrochloride, acetate, besylate, citrate, hydrobromide, D or L lactate, mesylate, succinate, sulfate, D or L tartrate, stearate, tosylate; a cation selected from calcium, potassium and sodium; and ethylenediamine.
In one aspect, the invention provides a process wherein said chemical compound to be formed is Ziparasidne hydrochloride monohydrate. In another aspect, this invention provides a process wherein one reactive intermediate is Ziprasidone free base and the other reactive intermediate is an aqueous hydrochloric acid solution.
In another aspect, the invention proves a process wherein said product to be formed is Voriconazole free base. In a further aspect, this invention provides a process wherein the basic intermediate is selected from, but not limited to, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and said acidic intermediate is Voriconazole R-(xe2x88x92)-camphorsulfonic acid salt.
In another aspect, this invention provides a process wherein the compound to be crystallized is 5,8,14-triazatetracyclo[10.3.1.02,11.04,9]-hexadeca-2(11),3,5,7,9-pentaene L-tartrate. Further, the invention relates to a process wherein the first reactive intermediate is the 5,8,14-triazatetracyclo[10.3.1.02,11.04,9]-hexadeca-2(11),3,5,7,9-pentaene free base and the second reactive intermediate is L-tartaric acid.
In another aspect, this invention provides a process wherein the desired product is in the form of crystalline aggregates which are of controlled size. In another aspect the invention provides a process wherein the linear velocity of jet streams is at least 5 m/sec. In a further aspect, the invention provides a process wherein said product is solvated. In another aspect, this invention provides a sonication probe along with impinging jets to achieve high intensity micromixing.